CA2875147A1 — Method of preparing crystalline form phthalazinone derivative for use in cancer treatment

USPTO Abstract

The present invention is directed to a method of synthesising 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one from 2-carboxybenzaldehyde, comprising the steps of: (a) synthesising diethyl (3-oxo-1,3-dihydro-2-benzofuran-1-yl)phosphonate from 2-carboxybenzaldehyde; (b) synthesising 2-fluoro-5-[(E/Z)-(3-oxo-2-benzofuran-1(3H)-ylidene)methyl]benzonitrile (from diethyl (3-oxo-1,3-dihydro-2-benzofuran-1-yl)phosphonate; (c) synthesising 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile from 2-fluoro-5-[(E/Z)-(3-oxo-2-benzofuran-1(3H)-ylidene)methyl]benzonitrile by reaction with hydrazine hydrate; (d) synthesising 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoic acid from 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile by reaction with sodium hydroxide; (e) reacting 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoic acid with 1-(cyclopropylcarbonyl)piperazine or a mineral acid salt thereof in the presence of an amide coupling agent. The compounds obtained are useful as intermediates and as components of pharmaceutical compositions.